Tertiaryamino butynyl alcohols



United States Patent 3,086,021 v TERTIARYAMINO BUTYNYL ALCOHOLS John H. Biel, Milwaukee, Wis-,assignor, by rnesne assignments, to Lakeside Laboratories, Inc., Milwaukee,

Wis., a corporation of Delaware No Drawing. Filed Sept. 20, 1957, Scr. No. 685,091 10 Claims. (Cl. 260-268) This invention is related to acetylene compounds. More particularly, it is concerned with novel 4-amino-2-butynes and methods of producing such compounds.

This application is a continuation-in-partof my application Serial No. 602,527, filed August 7, 1956 now abandoned.

There are provided according to the present invention novel 1',l-dicyclic 4 disubstituted .amind-Z-butyne-l-ol compounds of the formula and acid addition and quaternary ammonium salts thereof, wherein R is a phenyl or nuclear substituted phenylgroup such as a lower .alkoxy phenyl, lower alkyl phenyl, hyd-roxyphenyl or halophenyl group, or a thienyl, pyridyl, or lower cy'cloalkyl group such'as cyclohexyl or cyclopentyl, and R is a thienyl, pyridyl or furyl group, R is hydrogen or a lower alkyl group and R and R are the same or different alkyl groups, preferably lower alkyls," aryl groups, preferably monocyclic aryl groups such as the phenyl group, aralkyl groups, preferably lower alkylmonocyclic aryl groups like benzyl and phenethyl groups, alkeny-l groups, preferably lower alkenyls such as the allyl group and groups in which R, and R are joined to form a heterocyclic ring, preferably of 5 or 6 atoms in the ring such as pyrrolidino, piperidino, piperazino and morpholino.

These compounds, as the bases, may be conveniently produced by reacting an appropriate dicyclic ketone with a reactive metal salt, such as an alkali metal salt, of an appropriate tertiary aminopropyne. This process may be represented as follows:

wherein A is a reactive metal and R R R R and R have the significance assigned above.

Representative dicyclic ketones which may beempl-oyed inthis reaction are 4-methoxyphenyl 2-thienyl ketone, 2-

ethylphenyl 4-pyridyl ketone, 4-hydroxyphenyl Z-thienyl "ketone, phenyl 2-thienyl ketone, cyclohexyl Z-thieny-l ketone, cyclopentyl 2-thieny1 ketone, phenyl 4-pyridyl ketone, phenylfuryl ketone and di-(2-thienyl) ketone.

Typical tertiary amiuopropynes such as 3-dimethylamino 1 propyne, S-diethylamino-l-propyne, B-pyrrolidino-l-propyne, 3-N-morpholinyl-1-propyne,. 3-piperidino-l-propyne, 3-diphenylamino-1-pnopyne, 3-diethylamino-3-methyl-1-propyne, and S-dibenzylamino-l-propyne may be employed in the reaction in the form of reactive metal salts such as the alkali metal salts. The sodium salts are readily prepared by reacting the propynyl- 3,086,021 Patented. Apr. 16, 1963 amine with sodamide at the reflux temperature of an inert solvent such as benzene.

The reaction is preferably carried out by contacting the reactants in the presence of an inert solvent, such as benzene or toluene, and. employing an elevated temperature, such as the reflux temperature, to effect reaction in a convenient amount of time. The desired product may be recovered from the reaction mixture by conventional procedures such as cooling the mixture as over ice and filtering off the product.

Some typical novel compounds produced by this method are 1phenyl- 1- (4-pyridyl) -4-diethylamino-Z-butyne-1-01,

l-phenyl- 1- Z-thienyl) -4-morpholino-2-butyne-1-01,

, l-phenyl-1-fuIy1-4-dimethylarnino2-butyne-1-ol,

l-phenyl- 1- (4-pyridyl) -4-pyrrolidino-2-butyne 1-o1, l-phenyl-l- Z-thienyl) -4- dimethylamiuo-Z-butyne-l -ol, l-phenyl- 1- (Z-thienyl) -4-diethylamino-2-butyne-1-01, l-phenyl- 1 (Z-thienyl) -4-pyrrolidino-2-butyne- 1 -ol, 1-cycl-ohexyl-1-(2-thienyl -4-diethylamino-2butyne-1-ol,

' 1-cyc1ohexyl-1-(2-thienyl -4-pyrrolidino-2butyne1-ol,

l-cyclopentyl- 1 Z-thienyl) -4-diethy1amino-2-butyne-1-o1,

l-cyolop entyl- 1- Z-thienyl) -4-pyrrolidino-2.-butyne-l-ol,

l-phenyl-1-(4-pyridyl) -4-dimethylamino-2-butyne-1-01,

1, 1- (4-pyridyl -4-diethylamino-4-ethyl-2-butyne-l-ol,

1,1-bis(2-thienyl) -4-pyrrolidino-2-butyne-l -ol and l-cyclohexyl-l- 2-thienyl) -4- 4-methylpiperazino) -2,-

butyne- 1 01.

. presence of a suitable organic solvent. Alkyl halides such as methyl bromide, ethyl iodide, methyl sulfate, benzyl chloride and propangyl bromide are representative compounds that may be used to form quaternary ammonium salts.

In the form of non-toxic acid addition salts the novel amino butynols are sedative and diuretic agents. The

non-toxic quaternary ammonium salts of these compounds are potent gastric anti-secretory agents useful in the therapy of peptic ulcer; in addition, they are potent antispasmodics, useful in relieving disturbances of the digestive tract.

' The following examples illustrate specific embodiments of the invention, but it is to be understood that these examples are for illustration only and are not to be considered as restricting the invention.

EXAMPLE 1 1 -CyclohexyZ-1 (Z-Thienyl) -4-Dimcthylamina-Z-Buiyne- To 7.8 g. (0.2.mole) of sodamide in cc. of benzene 'was added 17 g;'(0.2 mole) of dimethylamino propyne and the mixture heated at reflux for 1 hour. Then 38 g. (0.2 mole) of cyclohexyl Z-thienyl ketone was added and the mixture refluxed for 6 hours. It was poured over ing the appropriate reactants, the bases of Table 1 were ice and the solid which formed collected on a filter. The prepared.

TABLE 1 R1\(I)H Assay R1 R: Am M.P., Yield, Caled. Found 0. percent Percent Percent Percent Percent N(OH5)7 134-136 74 5.10 11.55 5. 08 11.00 C H 84 4. 00 1o. 74 4. 32 10.84 80 4.71 10.77 4.74 10.25 03 5.05 11.55 4.83 11.45 87 4. 59 10.49 4.57 10.48 81 4.52 10.55 4. 33 10.00

Pyrrolldino 90 4. 84 11. 07 0) -N (0114):. 95 10.52 10.18

1 Bases not isolated.

product was recrystallized from hot n-hexane. MI. 135- 136 C.; 51 g. (93%).

Analysis.-Calcd. C H NOS: 5.05% N; 11.55% S. Found: 4.83% N; 11.45% S.

In Table 2 there is set forth various data concerning quaternary ammonium salts of typical bases that have been prepared.

TABLE 2 B1 OH /(IJ-OECCHQAID.R3+X' 2 Assay R1 R1 R5 Am X M.P.C Yield, Calcd. Found percent Percent Percent Percent Percent Percent Percent N S X N S X Phenyl 2rthienyl CH; N(OH5)1-. Br 202-203 89 3.82 8.74 21.85 3.85 8.85 22.17 D CH5- -N (071192... Br 160-161 87 3. 8.12 20.36 3.57 8.16 20.69 CH3- Pyrrolidlno.-. I 143-144 94 3.19 7. 29 28. 93 3.04 7.24 30.05 CH;- N(CH4)1--.- I 175-177 93 3.34 7.63 30.31 3.79 7.54 29.47 CH;- N(C4H1)5.- I 106-168 90 3.13 7.16 28.41 2.93 7.20 28.14 CH:- Pyrrolidino.-. I 146-148 94 3.15 7.19 28. 53 2.95 7.22 28.51 0115- N(OH5)4 I 150-152 3.45 7.90 31.35 3.27 7.97 30.48

CH;- N(C1H5)5 I 110-112 3.23 7.30 20.33 3.01 7.58 28.00 CHT" Pyrrolidino... I -107 86 3.25 7.42 29.46 3.08 7.42 29.61

EXAMPLE 2 By following the procedure of Example 1 and employ- Table 3 sets forth data for bifumarate and fumarate salts of typical bases provided by this invention.

TABLE 3 C--OEO-OH4Am-HOOOCH=CH-OO0H []3lumarate] Assay M.P., Yield. Caled. Found R R2 Am C percent Per- Per- Per- Percent cent cent eesnt Cyclopentyl N(CH5)2 -126 83 3.69 8.44 3.06 8.26 D0 -N(C:H5)z..- 120-123 80 3.44 7.86 3.36 7.12 Pyrrolidln0 -132 90 3.46 7.90 3.35 7. 83

[Fumarate] Assay Yield percent Percent

Z-thienyl -.do 4-pyridyl Example 3 I -Cyclohexyl-1 (a-Thienyl) -4- (4'-Methyl-Piperazino) Z-Butyn-I-ol Cyclohexyl 2-thieny1 ketone was reacted with 3-(4'- methylpiperazino)-1-propyne as the sodium salt as in Example 1 to form this compound.

M.P. 133-135 C. Analysis.-Calcd. for C H N OS: N, 8.43; S, 9.63. Found: N, 8.15; S, 9.64.

The mono-methiodide salt melted at: 190-192 C. Analysis.-Calcd. for C H IN OS: N, 5.90; S, 6.75; I, 26.79. Found: N, 5.62; S, 6.64; I, 27.25.

The dimethiodide salt melted at: 204-206 C. Analysis.Calcd. for C H I N OS: N, 4.56; S, 5.21; I, 41.36. Found: N, 4.23; S, 5.07; I, 40.87.

The mono-fumarate salt melted at: 168-169 C. Anal- )SiSr-C31Cd. for C23H32N205S: N, S, 7-14. Found: N, 5.85; S, 6.74. I

Various changes and modifications of the invention can be made and, to the extent that such variations incorporate the spirit of this invention, they are intended to be included within the scope of the appended claims.

What is claimed is:

1. A member of the group consisting of compounds of the formula and non-toxic acid addition and non-toxic quaternary ammonium salts thereof, wherein R is a member of the group consisting of phenyl, lower alkoxy phenyl, lower alkyl phenyl, hydroxyphenyl, h alophenyl, thienyl, pyridyl, and lower cycloalkyl groups, R; is :a member of the group consisting of thienyl, pyridyl, and fury], R is a member of the group consisting of hydrogen and lower alkyl groups, and R and R are members of the group consisting of lower alkyl, phenyl, phenyl-lower alkyl and lower alkenyl groups, and groups in which R; and R are joined to form a heterocyclic ring of the group consisting of pyrrolidino, morpholino, piperidino and piperazino groups.

2. l-phenyl- 1-( Z-thienyl) -4-dimethylamino-2-butyne-1- 01.

3. l-phenyl-l-(Z-thienyl)-4-diethylamino-2-butyne-l-ol.

4. 1-phenyl-1-(2-thienyl)-4-pyrrolidino-2-butyne-1-ol.

5. 1-cyclohexyl-l-(2-thienyl)-4-diethylamino-2-butynel-ol.

6. l-cyclohexyl-l-(Z-thienyl)-4-pyrrolidino-2-butyne-1- ol.

7. l-cyclopentyl-1-(2-thienyl)-4-diethylamino-Z-butyne- 1-ol.

8. l-cyclopentyl-l-(2-thienyl)-4-pyrrolidino-2-butyne-1- ol.

9. 1-cyclohexyl-1-(a-thieny1)-4-(4-methylpiperazino)- Z-bu-tyne-l-ol.

10. 1 pheny1-1-(4-pyri-dyl)-4-dimethylamino-Z-butyne- 1-01.

References Cited in the file of this patent UNITED STATES PATENTS Ruddy et a1 June 1, 1954 Reppe et a1 Feb. 19, 1957 OTHER REFERENCES 

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF A FORMULA 